We generated mice with Gs-alpha deficiency in beta cells (betaGsKO mice) by repeated matings of rat insulin II promoter-cre recombinase transgenic mice with floxed Gs-alpha mice which have loxP recombination sites surrounding Gs-alpha exon 1. BetaGsKO mice have very poor survival during the first several weeks of life in most cases associated with hyperglycemia and in addition had very poor postnatal growth. Studies in adult mice showed that betaGsKO mice had severe hyperglycemia and glucose intolerance despite having greater than normal insulin sensitivity. Impaired glucose tolerance was due to the fact that these mice were hypoinsulinemic, with reduced islet insulin content and glucose-stimulated insulin release. Although islet architecture was maintained, betaGsKO mice had significantly reduced beta cell mass with reduced beta cell proliferation and increased beta cell apoptosis. Studies on younger mice show that beta cell proliferation is reduced from birth. Although studies have suggested that Gs-cAMP mediates these effects on beta cell growth, survival, and insulin release by stimulating insulin receptor substrate 2 (Irs2) expression, we observed no change in expression of Irs2 or Pdx1, a beta cell growth gene which is induced by Irs2 signaling. Rather, there was a specific reduction in cyclin D2 expression. Studies directly examining the effects of cAMP on expression of cyclin D2 promoter-reporter constructs in beta cells as well as cross breeding studies of betaGsKO mice with various mouse lines in which cell cycle genes have been knocked out are ongoing. More recently we have made a second mouse line with beta-cell Gs-alpha deficiency using Pdx1-cre. These mice have Gs-deficiency throughout the endocrine and exocrine pancreas. Results show these mice to also develop severe insulin-deficient diabetes. However these mice have more or less normal survival and there is a greater proportion of pancreatic alpha-cells in the islets with no evidence for reduced proliferation of these cells. Moreover studies in an alpha-cell line showed evidence that Gs-alpha leads to reduced proliferation of these cells, indicating that Gs-alpha may have opposite effects on proliferation of alpha- and beta-cells, respectively. Moreover, the exocrine pancreas was abnormal with enlarged ducts with large eosinophic cells, which may lead to GI malabsorption.